JOINT REPORTS ISSN 1977-7868

Cyclopropylfentanyl

EMCDDA–Europol Joint Report on a new psychoactive substance: N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl] cyclopropanecarboxamide (cyclopropylfentanyl)

In accordance with Article 5 of Council Decision 2005/387/JHA on the information exchange, risk assessment and control of new psychoactive substances

About this series EMCDDA–Europol Joint Report publications examine the detailed information provided by the EU Member States on individual new psychoactive substances. Information is collected from the Reitox network, the Europol national units and the national competent authorities of the European Medicines Agency. Each Joint Report serves as the basis upon which the decision to conduct a risk assessment of the new psychoactive substance is taken. It is part of the three-step procedure involving information exchange, risk assessment and decision-making in the framework of Council Decision 2005/387/JHA.

EMCDDA–Europol joint publication I Contents 3 I 1. Introduction 3 I 2. Information collection process 4 I 3. Information required by Article 5.2 of the Council Decision 4 I 3.1 Chemical and physical description, including the names under which the new psychoactive substance is known (Article 5.2(a) of the Council Decision) 6 I 3.2 Information on the frequency, circumstances and/or quantities in which a new psychoactive substance is encountered, and information on the means and methods of manufacture of the new psychoactive substance (Article 5.2(b) of the Council Decision) 6 I 3.2.1 Information provided to Europol 6 I 3.2.2 Information provided to the EMCDDA 7 I 3.3 Information on the involvement of organised crime in the manufacture or trafficking of the new psychoactive substance (Article 5.2(c) of the Council Decision) 8 I 3.4 A first indication of the risks associated with the new psychoactive substance, including the health and social risks, and of the characteristics of users — Article 5.2(d) of the Council Decision 8 I 3.4.1 Health risks 8 I 3.4.2 Serious adverse events 9 I 3.4.3 Characteristics of users 9 I 3.4.4 Social risks 9 I 3.5 Information on whether or not the new substance is currently under assessment, or has been under assessment, by the UN system (Article 5.2(e) of the Council Decision) 9 I 3.6 The date of notification on the Reporting Form of the new psychoactive substance to the EMCDDA or to Europol (Article 5.2(f) of the Council Decision) 10 I 3.7 Information on whether or not the new psychoactive substance is already subject to control measures at national level in a Member State (Article 5.2(g) of the Council Decision) 10 I 3.8 Further information (Article 5.2(h) of the Council Decision) 10 I 3.8.1 The chemical precursors that are known to have been used for the manufacture of the substance 10 I 3.8.2 The mode and scope of the established or expected use of the new substance 11 I 3.8.3 Other use of the new psychoactive substance and the extent of such use, the risks associated with this use of the new psychoactive substance, including the health and social risks 11 I 4. Information from the EMA (Article 5.3 of the Council Decision) 12 I 5. Conclusion 13 I References 15 I Annex 1

I Acknowledgements

The EMCDDA would like to thank the following for their contribution in producing this publication: || the Early Warning System (EWS) correspondents of the Reitox national focal points (NFPs) and experts from their national EWS networks; || the Europol national units (ENUs) and Europol Project Synergy; || the national competent authorities responsible for human and veterinary medicinal products in the Member States, Norway and Iceland; || the European Medicines Agency (EMA) and the European Commission; || the World Health Organization; || István Ujváry, hon. associate professor, Budapest University of Technology and Economics; hon. associate professor, University of Szeged; iKem BT, Budapest.

Project team: Anabela Almeida, Rachel Christie, Rita Jorge, Joanna de Morais, Sofía Sola, Katarzyna Natoniewska (EMCDDA) and Marike Weber (Europol). Project leaders: Ana Gallegos, Michael Evans-Brown and Roumen Sedefov (EMCDDA).

2 / 16 I 1. Introduction Information collected by Europol

Article 5.1 of Council Decision 2005/387/JHA (1) (hereinafter Europol asked the Europol national units to provide the ‘Council Decision’) stipulates that ‘Where Europol and the information on: EMCDDA, or the Council, acting by a majority of its members, consider that the information provided by the Member State ¡¡ the level of production of cyclopropylfentanyl in their on a new psychoactive substance merits the collection of country; further information, this information shall be collated and ¡¡ the level of distribution of cyclopropylfentanyl in their presented by Europol and the EMCDDA in the form of a Joint country; Report.’ The Joint Report shall be submitted to the Council of ¡¡ the level of trafficking of cyclopropylfentanyl in their the European Union, the European Medicines Agency (EMA), country, both for internal, transit, or export purposes; and the European Commission. ¡¡ the number of seizures of cyclopropylfentanyl in their country, the total amount of the seizures, country of origin, In September 2017, the EMCDDA and Europol examined and details on the physical forms (including photos); the available information on the new psychoactive ¡¡ the role of organised crime, or criminal groups, substance N-phenyl-N-[1-(2-phenylethyl)piperidin- in the production, distribution, and trafficking of 4-yl]cyclopropanecarboxamide, commonly known as cyclopropylfentanyl in their country; and, cyclopropylfentanyl, through a joint assessment based upon ¡¡ any known aspect of violence and/or money the following criteria: laundering relating to the production and trafficking of cyclopropylfentanyl. 1. the amount of the material seized; 2. evidence of organised crime involvement; Europol received responses from 20 Member States (2), the 3. evidence of international trafficking; Republic of Serbia, and Canada. 4. analogy with better-studied compounds; 5. evidence of the potential for further (rapid) spread; and, Information collected by the EMA 6. evidence of cases of serious intoxication or fatalities. According to Article 5.3 of the Council Decision, the EMA The EMCDDA and Europol agreed that the information requested that the national competent authorities responsible collected on cyclopropylfentanyl satisfied criteria 4 and 6. The for human and veterinary medicinal products in the two agencies therefore concluded that sufficient information Member States, Norway, Iceland, and Liechtenstein provide had been accumulated to merit the production of a Joint information on whether: Report on cyclopropylfentanyl as stipulated by Article 5.1 of the Council Decision. ¡¡ the new psychoactive substance cyclopropylfentanyl has obtained a marketing authorisation; ¡¡ the new psychoactive substance cyclopropylfentanyl is the subject of an application for a marketing authorisation; and, I 2. Information collection process ¡¡ a marketing authorisation that had been granted in respect to the new psychoactive substance cyclopropylfentanyl has In compliance with the provisions of the Council Decision, on 12 been suspended. October 2017 the EMCDDA and Europol launched a procedure for the collection of information on cyclopropylfentanyl, in order Twenty six countries provided a response to the EMA’s request to prepare the Joint Report. The information was collected regarding human and/or veterinary medicinal products (3). The mainly through the Reitox national focal points in the Member EMA also provided information as relevant to the centralised States, Turkey, Norway, as well as the Europol national units. In procedure for authorising human and veterinary medicinal addition, the EMA collected information through the national products. competent authorities responsible for human and veterinary medicinal products in the Member States as well as in Norway, (2) In alphabetical order: Austria, Bulgaria, Cyprus, Czech Republic, Denmark, Iceland, and Liechtenstein. The EMA also provided information Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Lithuania, as relevant to the centralised procedure for authorising Luxembourg, the Netherlands, Poland, Portugal, Slovenia, Spain, Sweden. (3) Austria, Belgium, Croatia, Estonia, Finland, Germany, Greece, Iceland, Ireland, medicinal products. The information collection process was Italy, Latvia, the Netherlands, Norway, Poland, Portugal, Slovakia, Slovenia, Spain, largely concluded by 23 November 2017. and Sweden provided a response in relation to human and veterinary medicinal products. Cyprus, the Czech Republic, Denmark, and Hungary provided a response in relation to human medicinal products. France, Romania and the (1) OJ L 127, 20.5.2005, p. 32. United Kingdom provided a response in relation to veterinary medicinal products.

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Furthermore, in anticipation of Article 7.3 of the Council 3. Information required by Article 5.2 Decision in relation to the manufacturing of medicinal I of the Council Decision products in the European Union, the EMA also requested information on whether the new psychoactive substance cyclopropylfentanyl is used to manufacture a medicinal The order and titles of subsections 3.1 to 3.8 and section 4, product: below, are as they appear in Article 5.2(a) to (h) and Article 5.3(a) to (c) of the Council Decision; sections are cross- ¡¡ which has been granted a marketing authorisation; referenced with those set down in the Council Decision. ¡¡ for which an application has been made for a marketing authorisation; and, ¡¡ for which a marketing authorisation has been suspended by a competent authority. 3.1 Chemical and physical description, including the names under which the new psychoactive substance Twenty six countries (4) provided a response to the EMA’s is known (Article 5.2(a) of the Council Decision) request in this regard. The EMA also provided information as I relevant to the centralised procedure for authorising human Chemical description and names and veterinary medicinal products. Cyclopropylfentanyl belongs to the 4-anilidopiperidine class of Information collected by the EMCDDA synthetic . This class also includes (5), which is internationally controlled, and a number of other fentanils. The EMCDDA collected information through: A total of 15 fentanils are controlled under the United Nations ¡¡ a structured questionnaire to the Reitox national focal Single Convention on Narcotic Drugs, 1961, as amended by points. The EMCDDA received replies from the 28 Member the 1972 Protocol (6). States, Turkey, and Norway; ¡¡ reports previously submitted to the European Union Early Cyclopropylfentanyl differs from fentanyl by Warning System, including EMCDDA–Europol Reporting replacement of the propionamide group of fentanyl with Forms, Progress Reports, and Final Reports; a cyclopropanecarboxamide group. Cyclopropylfentanyl ¡¡ routine monitoring of open source information; is also structurally related to (7), which is ¡¡ a specific information request to the World Health internationally controlled, and differs from butyrfentanyl Organization on whether or not cyclopropylfentanyl has by replacement of the butyramide group with been assessed or is under assessment by the United a cyclopropanecarboxamide group. Nations system; and, ¡¡ a search of open source information conducted specifically The synthesis of cyclopropylfentanyl has been described in for the production of the Joint Report which included: the patent literature (Janssen, 1968). scientific and medical literature, official reports, grey literature, internet drug discussion forums and related The molecular structure, molecular formula, and molecular websites (hereafter, ‘user websites’). mass of cyclopropylfentanyl are provided in in Figure 1.

Thus, the information included in sections 3.2.1 and 3.3 of the Joint Report was provided by Europol, while the EMCDDA provided information included in sections 3.1, 3.2.2, 3.4, 3.5, 3.6, 3.7, 3.8.1, 3.8.2, and 3.8.3 (in part). The information included in section 3.8.3 (in part) and section 4 was provided by the EMA.

(5) N-Phenyl-N​ -​[1-​(2-​phenylethyl)​piperidinyl-4-yl]propanamide (4) Austria, Belgium, Croatia, Estonia, Finland, Germany, Greece, Iceland, Ireland, (6) 3-Methylfentanyl, 3-methylthiofentanyl, acetyl-alpha-methylfentanyl, Italy, Latvia, the Netherlands, Norway, Poland, Portugal, Slovakia, Slovenia, Spain alpha-methylfentanyl, alpha-methylthiofentanyl, beta-hydroxy-3-methylfentanyl, and Sweden provided a response in relation to human and veterinary medicinal beta-hydroxyfentanyl, para-fluorofentanyl, thiofentanyl and are products. Cyprus, the Czech Republic, Denmark and Hungary provided controlled under Schedule I and IV; , fentanyl, , a response in relation to human medicinal products. France, Romania and the and butyrfentanyl are controlled under Schedule I. United Kingdom provided a response in relation to veterinary medicinal products. (7) N-Phenyl-N-[1-(2-phenylethyl)piperidinyl-4-yl]butanamide

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FIGURE 1 Molecular structure, molecular formula, and molecular mass of cyclopropylfentanyl. Information on butyrfentanyl and fentanyl is provided for comparison.

O O O

N N N

N N N

cyclopropylfentanyl butyrfentanyl fentanyl

Molecular formula C23H28N2O C23H30N2O C22H28N2O Molecular mass 348.49 350.51 336.48

Commonly used names: IUPAC International Chemical Identifier Key (InCHI Key) (9): cyclopropylfentanyl OIQSKDSKROTEMN-UHFFFAOYSA-N

Systematic (IUPAC) name: The REACH registered substances database hosted by the N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl] European Chemicals Agency (ECHA) was searched using the cyclopropanecarboxamide CAS registry number listed above. The searches returned no hits. Other chemical names: N-phenyl-N-[1-(2-phenylethyl)-4-piperidyl] Physical description cyclopropanecarboxamide; N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]- Cyclopropylfentanyl contains one basic nitrogen atom in the cyclopropanecarboxamide; piperidine ring which can readily form salts with organic or inorganic acids. N-(1-phenethylpiperidin-4-yl)-N- phenylcyclopropanecarboxamide; Limited solubility data available on cyclopropylfentanyl N-fenyl-N-[1-(2-fenyletyl)-4-piperidinyl] indicates that it is soluble in methanol; due to its similarity cyklopropankarboxamid (Swedish); to fentanyl, the free base could be expected to be sparingly N-(1-fenetylpiperidin-4-yl)-N-fenylcyklopropankarboxamid soluble in water; the hydrochloride and citrate salt could be (Swedish) expected to have greater aqueous solubility.

Other names and code names: Cyclopropylfentanyl is expected to be lipophilic. cyclopropyl fentanyl, cyclopropyl-fentanyl, cyclopropylfent The measured melting point of cyclopropylfentanyl was Street names reported as 119.5–120.4 °C (Janssen, 1968). ‘cyclopropyl’ (Belgium), ‘synthetic ’ (Belgium), Cyclopropylfentanyl has been detected in powders and, to ‘4-me-MAF’ (Sweden), a lesser extent, in liquids and in tablets. A more detailed ‘MAF’ (Poland) description of seizures and collected samples can be found in section 3.2.1 and section 3.2.2. Chemical Abstracts Service (CAS) registry numbers (8): 1169-68-2 free base

(8) The Chemical Abstract Service Registry Number (CAS RN) is a unique numeric identifier assigned by the Chemical Abstract Service Division of the (9) InChI Key is a unique, non-proprietary stuctural identifier of chemical American Chemical Society to a specific, single chemical substance. substances useful in electronic sources.

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Detection and analysis approach has been reported as characteristic for marketing fentanils in Sweden. Methods documented in the literature for the detection of cyclopropylfentanyl include: gas chromatography–mass The level of distribution spectrometry (GC-MS) (Slovenian National Forensic Limited information was received in relation to the distribution Laboratory, 2017; SWGDRUG, 2017), Fourier transform (seizures) of cyclopropylfentanyl (10). infrared spectroscopy attenuated total reflectance (FTIR-ATR) (Slovenian National Forensic Laboratory, 2017; SWGDRUG, Sweden reported 26 seizures of cyclopropylfentanyl since the 2017), gas chromatography–mass spectrometry–infrared substance was introduced on to the market. They reported spectroscopy (GC-(MS)-IR) condensed phase (Slovenian two ‘large seizures’ distributed via a postal-hub in Belgium. National Forensic Laboratory, 2017), and nuclear magnetic resonance (NMR) (SWGDRUG, 2017). Sweden reported that the substance is ordered from Swedish websites on the surface web and sent directly to There is no information on the reaction of cyclopropylfentanyl the end user, or, in some cases, to relatives of the user. They to presumptive colour tests. also reported that there is no information to indicate that Swedish customers use cyclopropylfentanyl purchased from Cyclopropylfentanyl is not expected to give a positive international websites. response to immunoassays developed for -type opioids. It is unknown if immunoassays for fentanyl will detect As part of an ongoing investigation, it is estimated that 600 cyclopropylfentanyl. In addition, it is unknown whether such people have purchased cyclopropylfentanyl from a specific assays can distinguish between cyclopropylfentanyl and webpage. However, it is not possible to confirm that all the fentanyl (US DEA, 2017b). Identification of cyclopropylfentanyl purchases involved cyclopropylfentanyl. Cyclopropylfentanyl requires confirmatory analysis (US DEA, 2017b). was reported to be available in Sweden as of 13 June 2017; a death associated with cyclopropylfentanyl was also reported on the same day.

3.2 Information on the frequency, circumstances and/or The level of trafficking quantities in which a new psychoactive substance is Limited information was received in relation to the trafficking encountered, and information on the means and of cyclopropylfentanyl. methods of manufacture of the new psychoactive substance (Article 5.2(b) of the Council Decision) Sweden reported that the domestic postal service is used for I the distribution of the substance which is ordered from China The data reported to Europol discussed in section 3.2.1 may in powder form and then distributed to buyers via domestic overlap with the data reported to the EMCDDA discussed in postal services. There is no information to indicate that the section 3.2.2. substance is exported from Sweden.

3.2.1 Information provided to Europol 3.2.2 Information provided to the EMCDDA

Europol received replies from 20 Member States (Austria, The EMCDDA received responses from the 28 Member Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, States, Turkey, and Norway. Of these, 5 Member States France, Germany, Greece, Hungary, Ireland, Lithuania, (Austria, Latvia, Poland, Sweden, and the United Kingdom) Luxembourg, the Netherlands, Poland, Portugal, Slovenia, and Norway reported detections of cyclopropylfentanyl (11). Spain and Sweden), the Republic of Serbia, and Canada. (10) Canada reported two seizures of cyclopropylfentanyl. One seizure of 11 The level of production grams of white powder originated in China and was concealed in bags of dog food/treats. The analysis confirmed the citrate salt of cyclopropylfentanyl No information was received in relation to the production of (N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]cyclopropanecarboxamide). The cyclopropylfentanyl. second seizure was 268 grams of white powder, which originated in Hong Kong and, unlike the previous seizure, was not concealed. The analysis confirmed and cyclopropylfentanyl.. Sweden reported that there is no known production of (11) ‘Detections’ is an all-encompassing term and may include seizures and/or collected and/or biological samples that are analytically confirmed. Seizure cyclopropylfentanyl in the country. Vendors mix the substance means a substance available (seized) through law enforcement activities (police, in powder form with water and then they package the resulting customs, border guards, etc.). Collected samples are those that are actively solution into nasal spray bottles, ordered from China. This collected by drug monitoring systems (such as test purchases) for monitoring and research purposes. Biological samples are those from human body fluids (urine, blood, etc.) and/or specimens (tissues, hair, etc.).

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Images of seizures and collected samples reported to the Tablets EMCDDA are provided in Annex 1. A total of 87 tablets containing cyclopropylfentanyl were seized in 4 cases that were reported by Sweden. It is important to note that cyclopropylfentanyl may be under- detected since the substance is not routinely screened for. Collected samples Three Member States (Belgium, Slovenia, and Sweden) and A total of 4 collected samples containing cyclopropylfentanyl Norway reported that cyclopropylfentanyl is part of routine were reported by 3 Member States (Austria, Poland, and the screening in some (but not all) laboratories. United Kingdom) and Norway. All the samples were collected between June and October 2017. Seizures In total, 57 seizure cases (12) were reported to the EMCDDA by In the two cases reported by Austria and the United Kingdom, 4 Member States: Latvia (25 cases), Poland (2), Sweden (27), the samples were purchased as a powder from the internet. In and the United Kingdom (3). Where known, the seizures took the case reported by the United Kingdom, acetylfentanyl was place between July and November 2017 and were made by also detected in the powder. police or customs agencies. In the case reported by Poland, the sample was collected from Cyclopropylfentanyl was detected in powders, and, a user and was sold as ‘MAF’. to a lesser extent, in liquids and in tablets. Aside from cyclopropylfentanyl, no other substances were reported to In the case reported by Norway, cyclopropylfentanyl was have been detected in the seizures. detected in a liquid in a nasal spray that was recovered from the scene of a death. Both cyclopropylfentanyl and Powders acetylfentanyl were detected in the liquid as well as in A total of 1.6 kg of powder containing cyclopropylfentanyl was a biological sample from the deceased (see section 3.4.1). It seized in 26 cases that were reported by Latvia (18 cases), was reported that the user had used a ‘methoxyacetylfentanyl Poland (2), Sweden (4), and the United Kingdom (2). Where nasal spray’. known, the powders were reported to be white or off-white in colour. Biological samples Serious adverse events with confirmed exposure to In 23 cases, the quantities seized were less than 5 g. However, cyclopropylfentanyl from biological samples are discussed in in a case reported by Poland, two samples amounting to section 3.4.2. approximately 500 g each were seized. In this case, the substance was seized by Polish customs in parcels sent by In addition to these, Sweden reported a suspected petty drug post from China (via Belgium) to a private address in Poland offence where cyclopropylfentanyl was analytically confirmed in September 2017 (Annex 1); while in a case reported by in a biological sample; the case occurred in September 2017. Sweden, approximately 600 g was seized by customs (no additional details are available).

Liquids 3.3 Information on the involvement of organised A total of 240 mL of liquid containing cyclopropylfentanyl was crime in the manufacture or trafficking of the new seized in 27 cases that were reported by Latvia (7 cases), psychoactive substance (Article 5.2(c) of the Council Sweden (19), and the United Kingdom (1). I Decision) The quantity seized ranged from 0.1 to 49 mL. In the cases No information concerning the involvement of organised reported by Latvia the liquids were recovered from syringes. crime in the manufacture and/or trafficking of the In the case reported by the United Kingdom, a nasal spray cyclopropylfentanyl was provided. containing 3.8 mL of a liquid containing cyclopropylfentanyl was seized. Sweden reported that the availability of cyclopropylfentanyl can be linked to two known vendors who sell substances on several domestic websites on the surface web. These vendors are both known to police and have been previously convicted

(12) Many ‘seizures’ relate to individual cases, however, some data provided to the of serious drug offences. It is thought that the vendors have EMCDDA are aggregated at the country level. Data is drawn from the Joint contacts in China but it is unknown whether they use the Report Questionnaires and data provided in the bi-annual data gathering (EU same source for their products. EWS Progress Reports and Final Reports) and from individual EMCDDA–Europol Reporting forms submitted to the EMCDDA on an ad hoc basis.

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Money laundering aspects opioids, benzodiazepines, gabapentanoids, and alcohol); Limited information was received in relation to the money a lack of tolerance to opioids; and, using the substance alone laundering in connection with the production and/or (such as at home) which would make it more difficult for users trafficking of cyclopropylfentanyl. to call for help in the case of poisoning.

Sweden reported that the known vendors for fentanils in Available information shows that fentanils are being sold to the Swedish domestic market sell the substances through users in or as heroin or other illicit opioids, as well as used established companies and that payment is through bank to make counterfeit (fake) medicines (such as fake transfer, cash on delivery, bitcoin, or Swish (13). They (‘pain killers’) and benzodiazepines). They may also reported that money laundering is considered an element in be sold as or in other illicit drugs such as cocaine. As users will those cases. In addition, the sale of fentanils in Sweden is be unaware of this, it could increase the risk of life-threatening considered to be very profitable due to the relatively low cost poisoning in opioid users and especially other user groups of purchasing and distributing the substances compared to (such as cocaine users) who may have no existing tolerance to the financial gains. opioids

Violence in connection with production, wholesale and The antidote should reverse the respiratory distribution depression and other features of acute poisoning caused No information was received on incidents of violence in by cyclopropylfentanyl (Kim and Nelson, 2015; Ujváry et connection with the production, wholesale, and/or trafficking al., 2017). Recent clinical and community experience in of cyclopropylfentanyl. treating poisonings caused by fentanils suggests that larger than normal doses and repeated doses of naloxone may be required to manage the poisoning in some cases; longer periods of observation may also be required (EMCDDA, 2017). 3.4 A first indication of the risks associated with the new psychoactive substance, including the health and While there is limited data for cyclopropylfentanyl, the chronic social risks, and of the characteristics of users — health risks might share some similarities to opioids such as I Article 5.2(d) of the Council Decision heroin and other fentanils. This may include dependence.

3.4.1 Health risks 3.4.2 Serious adverse events

Limited data suggests that cyclopropylfentanyl is a μ-opioid Acute intoxications reported to the EMCDDA receptor agonist that shares some similarities with opioid No acute intoxications with confirmed exposure to analgesics such as morphine and fentanyl (Janssen and Van cyclopropylfentanyl were reported to the EMCDDA (14). der Eycken, 1968; US DEA, 2017a; US DEA, 2017b). Deaths reported to the EMCDDA The acute effects of these types of opioids include: euphoria, In total, 60 deaths with confirmed exposure to relaxation, analgesia, sedation, bradycardia, hypothermia, and cyclopropylfentanyl were reported to the EMCDDA by Sweden respiratory depression. They also have an abuse liability and (59 cases) and Norway (1 case). In addition, Latvia reported dependence potential (Herz, 1993; Kieffer, 1999, Pasternak 4 deaths with possible exposure to cyclopropylfentanyl (15); and Pan, 2013; Pattinson, 2008; Romberg et al., 2003). these 4 cases are not discussed further in this report.

Similar to other opioid analgesics, the most serious acute The 60 deaths occurred between June and October 2017. health risk from using cyclopropylfentanyl is probably Of these, 55 (92 %) were male and 5 (8 %) were female. respiratory depression, which in overdose could lead to The males were aged between 21 and 59 years (mean 33.2; apnoea, respiratory arrest, and death (EMCDDA, 2017; median: 32); the females were aged between 25 and 32 Pattinson, 2008; White and Irvine, 1999). This risk may be years (mean: 29; median: 30). A range of other substances greater due to: the difficulty in diluting the substance; a lack of were detected in the deaths, including other central nervous experience with its effects and dosing; the use of other central system depressants. Other opioids were detected in 16 cases; nervous system depressants at the same time (such as other

(14) Sweden reported 2 acute intoxications with suspected exposure to cyclopropylfentanyl. These cases are not discussed further in this report. (13) Swish is a mobile app payment system which allows users to send money (15) Latvia reported 4 deaths where syringes containing cyclopropylfentanyl using a mobile phone connected to an online banking service. Swish is where found next to the deceased. Analytical confirmation of exposure from a payment system used between bank accounts in Sweden. biological samples is not available.

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in only one of these cases was another fentanil detected 3.5 Information on whether or not the new substance (acetylfentanyl). In all of the cases the decedents were is currently under assessment, or has been under either found dead or unconscious, predominantly in a home assessment, by the UN system (Article 5.2(e) of the environment. I Council Decision) The cause of death was reported for 24 cases. In 23 cases, The World Health Organization is the specialised United cyclopropylfentanyl was the cause of death or contributed to Nations agency designated for the evaluation of the medical, the death. scientific, and public health aspects of psychoactive substances under the Single Convention on Narcotic Drugs, Serious adverse events identified in open source 1961, and the Convention on Psychotropic Substances, 1971. information During 2017, more than 100 deaths associated with On 22 October 2017, the World Health Organization informed cyclopropylfentanyl were reported in the United States (US the EMCDDA that cyclopropylfentanyl is currently not under DEA, 2017b; Smith and Kinkaid, 2017) (16). assessment and has not been under assessment by the UN system.

3.4.3 Characteristics of users

Similar to other new fentanils, cyclopropylfentanyl is sold and 3.6 The date of notification on the Reporting Form of used as a ‘legal’ substitute for illicit opioids and prescription the new psychoactive substance to the EMCDDA or opioids medicines; this may include for self-medication, such to Europol (Article 5.2(f) of the Council Decision) as the alleviation of pain and/or opioid withdrawal. Users I may include high-risk drug users as well as others (such as The first official EMCDDA–Europol notification of psychonauts) who may be experimenting with the substance. cyclopropylfentanyl dates from 4 August 2017 from the Latvian national focal point. The Reporting Form details the seizure of cyclopropylfentanyl in 34.5 mg of white 3.4.4 Social risks powder, seized by the police in Riga on 25 July 2017. The substance was analytically confirmed by the Forensic Service While there is limited data for cyclopropylfentanyl, the social Department of the State Police by GC-MS, and a library match risks might share some similarities with opioids such as heroin with the Cayman Spectral Library. and other fentanils. Cyclopropylfentanyl was added to the list of new psychoactive Of additional note is that in the past few years fentanils substances monitored by the EMCDDA and Europol through have been sold in Europe as ready-to-use nasal sprays and the European Union Early Warning System. A profile of e-liquids for vaping. In general, these novel products could the substance was created on the European Database make it easier to use such substances (with similar effects to on New Drugs (EDND). Since then, analytical details and injecting) and make them more socially acceptable. Further other information, including a public health alert, have been research is required on this topic to better understand the exchanged between the EMCDDA, Europol, and the Member risks. States, Turkey, and Norway, on an ad hoc basis; the European Commission and the EMA have been kept duly informed. Similar to other fentanils, accidental exposure to cyclopropylfentanyl may also pose a risk of poisoning. Those Of note is that data from biological samples related at risk may include the family and friends of users, law to death cases reported to the EMCDDA shows that enforcement, emergency personnel, medical and forensic cyclopropylfentanyl has been on the market in Europe since at laboratory personnel, as well as those in custodial settings least June 2017. and postal services. Where required, these risks should be assessed and appropriate procedures, training, and protective measures should be implemented. This may include training in resuscitation and adequate provision of the antidote naloxone (IAB, 2017; White House National Security Council, 2017).

(16) In addition, an outbreak of poisonings that involved 26 non-fatal intoxications and 1 death was associated with counterfeit Percocet tablets that contained cyclopropylfentanyl and U-47,700 in Georgia during June 2017 (Edison et al., 2017).

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3.7 Information on whether or not the new fentanyl are applicable to the synthesis of cyclopropylfentanyl. psychoactive substance is already subject to control Use of a different acylating agent in the final acylation step, measures at national level in a Member State (Article such as cyclopropanecarbonyl chloride would produce 5.2(g) of the Council Decision) cyclopropylfentanyl. A one-step method uses ANPP and I cyclopropanecarbonyl chloride for the manufacture of the Eight Member States (Cyprus, Estonia, Finland, Ireland, Latvia, substance. Lithuania, Sweden, and the United Kingdom) and Norway reported that cyclopropylfentanyl is controlled under drug France reported that aniline, NPP, ANPP, and control legislation. cyclopropanecarbonyl chloride could be used as potential precursors for the synthesis of cyclopropylfentanyl. Five Member States (Austria, Belgium, Germany, Hungary, and Poland) reported that cyclopropylfentanyl is controlled under Most of the synthetic procedures that could be used for specific new psychoactive substances control legislation. the synthesis of cyclopropylfentanyl are straightforward and use common laboratory equipment and precursors. Fifteen Member States (Bulgaria, Croatia, Czech Republic, Detailed methods are available on the internet (18). While Denmark, France, Greece, Italy, Luxembourg, Malta, the only basic knowledge of synthetic chemistry is required, Netherlands, Portugal, Romania, Slovakia, Slovenia, and due to the potency of fentanils extreme caution is required Spain) and Turkey reported that cyclopropylfentanyl is not when carrying out the final synthetic step as well as when subject to control measures at the national level. purifying and handling the substance. Exposure of the skin and mucous membranes to fentanils as well as their inhalation pose a serious risk of accidental poisoning. In addition to exercising extreme caution, suitable personal protective 3.8 Further information (Article 5.2(h) of the Council equipment as well as sufficient stocks of naloxone as an I Decision) antidote to poisoning following accidental exposure should be available when handling materials suspected to contain these substances (IAB, 2017; White House National Security 3.8.1 The chemical precursors that are known to have Council, 2017). been used for the manufacture of the substance In summary, the synthesis of cyclopropylfentanyl has been No information was reported by the Member States, Turkey, described in the literature. In addition, other routes developed or Norway about the chemical precursors or manufacturing for the manufacture of fentanyl may also be used. There is no methods used to make the cyclopropylfentanyl which has information on the actual method(s) used for the production of been detected within Europe. cyclopropylfentanyl that has been detected in Europe to date.

Two potential precursors of fentanyl and other fentanils — 4-anilino-N-phenethylpiperidine (ANPP) as well as 3.8.2 The mode and scope of the established or N-phenethyl-4-piperidone (NPP, a pre-precursor) — expected use of the new substance have been recently scheduled under the United Nations Convention against Traffic in Narcotic Drugs and Psychotropic No studies were identified that have examined the mode and Substances, 1988 (17). scope of established or expected use of cyclopropylfentanyl. Given the limited information currently available, the relevant The synthesis of cyclopropylfentanyl has been described information has been included in the previous sections. in the literature (Janssen, 1968) and the method included the use of ‘β-phenyl-ethyl’ and ‘N-(4-piperidyl)-N-phenyl- cyclopropanecarboxamide’.

The manufacture of cyclopropylfentanyl can also rely on precursors and synthetic methods similar to those used for the manufacture of pharmaceutical fentanyl (Casy and Huckstep, 1988; Gupta et al., 2013; Zee and Wang, 1980). Therefore, the methods developed for the synthesis of

(18) The detailed description of the most common procedure, referred to as the (17) Table I of the United Nations Convention against Traffic in Narcotic Drugs and ‘Siegfried method’, is readily available on the internet (see, for example, http:// Psychotropic Substances, 1988. opioids.com/fentanyl/synthesis.html).

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3.8.3 Other use of the new psychoactive substance 4. Information from the EMA and the extent of such use, the risks associated with I (Article 5.3 of the Council Decision) this use of the new psychoactive substance, including the health and social risks Twenty-three countries (Austria, Belgium, Croatia, Cyprus, No information was provided by the Member States, Turkey, or Czech Republic, Denmark, Estonia, Finland, Germany, Greece, Norway that indicated that cyclopropylfentanyl had any other Hungary, Iceland, Ireland, Italy, Latvia, the Netherlands, use apart from in analytical reference materials and scientific Norway, Poland, Portugal, Slovakia, Slovenia, Spain, and research. Sweden) reported that:

From the available information, it does not appear that ¡¡ cyclopropylfentanyl has not been granted a marketing cyclopropylfentanyl is used in the manufacture of a medicinal authorisation as a medicinal product for human use; product in the European Union. However, the data collection is ¡¡ cyclopropylfentanyl is not the subject of an application for incomplete and some countries indicated that this information a marketing authorisation as a medicinal product for human is not known. It is understood that the collection of such use; information is a challenge in the absence of a database on the ¡¡ there had been no cases of suspended marketing synthetic route of all medicinal products. authorisation in respect to cyclopropylfentanyl as a human medicine. Ten countries (Austria, Belgium, Croatia, Czech Republic, Denmark, Finland, Germany, Greece, Latvia, and the Twenty-two countries (Austria, Belgium, Croatia, Estonia, Netherlands) reported that cyclopropylfentanyl is not used Finland, France, Germany, Greece, Iceland, Ireland, Italy, to manufacture a medicinal product for human use. Thirteen Latvia, the Netherlands, Norway, Poland, Portugal, Romania, countries (Cyprus, Estonia, Hungary, Iceland, Ireland, Italy, Slovakia, Slovenia, Spain, Sweden, and the United Kingdom) Norway, Poland, Portugal, Slovakia, Slovenia, Spain, and reported that: Sweden) reported that it was unknown if cyclopropylfentanyl is used to manufacture a medicinal product for human use. ¡¡ cyclopropylfentanyl has not been granted a marketing authorisation as a medicinal product for veterinary use; In addition, the EMA reported that it is not known if ¡¡ cyclopropylfentanyl is not the subject of an application cyclopropylfentanyl is used in the manufacture of medicinal for a marketing authorisation as a medicinal product for products for human use and which are centrally authorised veterinary use; within the European Union. ¡¡ there had been no cases of suspended marketing authorisation in respect to cyclopropylfentanyl as Ten countries (Austria, Belgium, Croatia, Finland, France, a veterinary medicine. Greece, Latvia, Poland, Romania, and the United Kingdom) provided information that cyclopropylfentanyl is not used to The EMA also reported that cyclopropylfentanyl: manufacture a medicinal product for veterinary use. Twelve countries (Estonia, Germany, Iceland, Ireland, Italy, the ¡¡ has not been granted a marketing authorisation as Netherlands, Norway, Portugal, Slovakia, Slovenia, Spain, and a medicinal product for neither human nor veterinary use Sweden) reported that it was unknown if cyclopropylfentanyl through the centralised procedure; is used to manufacture a medicinal product for veterinary use. ¡¡ is not the subject of an application for a marketing authorisation for neither human nor veterinary use through In addition, the EMA reported that it is not known if the centralised procedure; cyclopropylfentanyl is used in the manufacture of medicinal ¡¡ is not the subject of a suspended marketing authorisation products for veterinary use and which are centrally authorised for neither human nor veterinary use through the within the European Union. centralised procedure.

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I 5. Conclusion Cyclopropylfentanyl is sold and used as a substitute for illicit opioids and prescription opioids. Similar to other fentanils, Cyclopropylfentanyl belongs to a group of synthetic opioids serious concerns exist that the substance could be supplied known as the fentanils. It is closely related to fentanyl, which surreptitiously to a range of drug users. is controlled under the United Nations Single Convention on Narcotic Drugs, 1961. Data suggests that cyclopropylfentanyl Cyclopropylfentanyl has not been assessed within the may be an opioid narcotic in humans, and, as such, United Nations system nor is it currently under assessment. may have an abuse liability and dependence potential; overall, Cyclopropylfentanyl is not subject to control measures in 15 these effects may be broadly comparable to fentanyl. The Member States and Turkey. most serious acute health risk posed by cyclopropylfentanyl is likely to be respiratory depression, which in overdose is Cyclopropylfentanyl does not appear to have any recognised life-threatening. The antidote naloxone should reverse this human or veterinary medical use in the European Union. respiratory depression. We conclude that the health and social risks caused by the Cyclopropylfentanyl has been available in the European Union manufacture, trafficking, and use of cyclopropylfentanyl, since at least June 2017. It has been detected in 5 Member as well as the involvement of organised crime and possible States and Norway where it has been seized as a powder, consequences of control measures, could be thoroughly liquids, and tablets. While the detected quantities are assessed through a risk assessment procedure in accordance relatively small, they include 3 seizures of bulk quantities of with Article 6 of Council Decision 2005/387/JHA. powder weighing approximately between 500 and 600 g each. Overall, the quantities detected should be seen within the The EMCDDA and Europol will continue to intensively monitor context of the high potency that is typical of the fentanils. cyclopropylfentanyl in order to ensure that new information is provided to the Member States, the EMA, and the Commission There are indications that the cyclopropylfentanyl currently via the information exchange of the European Union Early available on the market is synthesised by chemical companies Warning System. based in China. Cyclopropylfentanyl is sold online often under the guise of a ‘research chemical’. It is available, and, has been seized, in wholesale amounts and in consumer amounts.

A total of 60 deaths with confirmed exposure to cyclopropylfentanyl have been reported to the EMCDDA by Sweden (59 cases) and Norway (1). In at least 23 of the deaths, cyclopropylfentanyl was the cause of death or contributed to the death.

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References

I Casy, A. F. and Huckstep, M. R., (1988), ‘Structure-activity studies of fentanyl’. Journal of Pharmacy and Pharmacology, 40(9), pp. 605–608. https://doi.org/10.1111/j.2042-7158.1988.tb05318.x I Edison, L., Erickson, A. and Smith, S., et al. (2017), ‘Notes from the field: Counterfeit Percocet–related overdose cluster — Georgia, June 2017’, MMWR Morbidity and Mortality Weekly Report, 66(41), pp. 1119–1120. http://dx.doi.org/10.15585/mmwr.mm6641a6 I EMCDDA (2017), Risk assessment report on a new psychoactive substance: N-phenyl-N-[1-(2- phenylethyl)piperidin-4-yl]furan-2-carboxamide (furanylfentanyl), Publications Office of the European Union, Luxembourg. https://doi.org/10.2810/716236 I Gupta, P. K., Yadav, S. K., Bhutia, Y. D., Singh, P., Rao, P., Gujar, N. L., Ganesan, K. and Bhattacharya, R., (2013), ‘Synthesis and comparative bioefficacy of N-(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice’, Medicinal Chemistry Research, 22(8), pp. 3888–3896. https://doi.org/10.1007/s00044-012-0390-6 I Herz, A. (ed)., (1993). Opioids II. Springer-Verlag, Berlin. I Janssen, P. A. J. and Van der Eycken, C. A. M. (1968), ‘The chemical anatomy of potent morphine-like analgesics’, In: Burger, A. (Ed.), Drugs affecting the central nervous system, Volume 2, Marcel Dekker, Inc., New York, pp. 25–60. I Janssen PA, inventor; Res Lab Dr C Janssen NV, assignee. N-(1-alkyl-4-piperidyl)-N- arylalkanoamides. European patent FR 1517671 (A). 1968 March 22. https://worldwide.espacenet. com/publicationDetails/originalDocument?CC=FR&NR=1517671A&KC=A&FT=D&ND= 3&date=19680322&DB=EPODOC&locale=en_EP# I Kieffer, B. L., (1999), ‘Opioids: first lessons from knockout mice’, Trends in Pharmacological Sciences, 20, 19–26. https://doi.org/10.1016/S0165-6147(98)01279-6 I Kim, H. K. and Nelson, L. S., (2015), ‘Reducing the harm of opioid overdose with the safe use of naloxone: a pharmacologic review’, Expert Opinion on Drug Safety, 14(7), 1137–1146. https://doi.org /10.1517/14740338.2015.1037274 I Pasternak, G. W. and Pan, Y. X., (2013), ‘Mu opioids and their receptors: evolution of a concept’, Pharmacological Reviews, 65(4), pp. 1257–1317. https://doi.org/10.1124/pr.112.007138 I Pattinson, K. T., (2008), ‘Opioids and the control of respiration’, British Journal of Anaesthesia, 100(6), pp. 747–758. https://doi.org/10.1093/bja/aen094 I Romberg, R., Sarton, E., Teppema, L., Matthes, H. W. D., Kieffer, B. L. and Dahan, A., (2003), ‘Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and μ- deficient mice’, British Journal of Anaesthesia, 91, pp. 862–870. https://doi.org/10.1093/bja/aeg279

Slovenian National Forensic Laboratory (2017), ‘Analytical report cyclopropyl fentanyl C H 8N2O) I ( 23 2 N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl]cyclopropanecarboxamide’, NPS and related compounds – analytical reports. European project RESPONSE to challenges in forensic drugs analyses. ht tps:// www.policija.si/apps/nfl_response_web/0_Analytical_Reports_final/Cyclopropyl%20fentanyl- ID-1850-17_repor t.pdf I Smith, A. and Kinkaid, D. (2017), ‘Fentanyl and designer opioid-related deaths in Allegheny County’, ToxTalk, 41(3), pp. 6–8. I SWGDRUG, 2017, ‘Cyclopropyl Fentanyl’ monograph: http://www.swgdrug.org/Monographs/ Cyclopropyl%20fentanyl.pdf I Ujváry, I., Jorge, R., Christie, R., Le Ruez, T., Danielsson, H. V., Kronstrand, R., Elliott, S., Gallegos, A., Sedefov, R., Evans-Brown, M. (2017), ‘Acryloylfentanyl, a recently emerged new psychoactive substance: a comprehensive review’, Forensic Toxicology, 35, pp. 232–243. https://doi.org/10.1007/ s11419-017-0367-8

13 / 16 JOINT REPORTS I Cyclopropylfentanyl

I United States Drug Enforcement Administration (US DEA) (2017a), ‘N-(1-Phenethylpiperidin-4-yl)-N- phenylcyclopropanecarboxamide (cyclopropyl fentanyl). Temporary placement of cyclopropyl fentanyl into schedule I’, Federal Register, 82(223), pp.55333–55336. I United States Drug Enforcement Administration (US DEA) (2017b). N-(1-Phenethylpiperidin-4-yl)-N- phenylcyclopropanecarboxamide (cyclopropyl fentanyl). Background information and evaluation of ‘three factor analysis’ (factors 4, 5, and 6) for temporary scheduling. Drug and Chemical Evaluation Section, Office of Diversion Control, Drug Enforcement Administration, Washington, DC. October 2017. https://www.regulations.gov/document?D=DEA-2017-0013-0003 I United States InterAgency Board for Equipment Standardization and Interoperability (IAB) (2017). Recommendations on selection and use of personal protective equipment and decontamination products for first responders against exposure hazards to synthetic opioids, including fentanyl and fentanyl analogues. https://www.interagencyboard.org/sites/default/files/publications/IAB%20 First%20Responder%20PPE%20and%20Decontamination%20Recommendations%20for%20 Fentanyl.pdf I White House National Security Council (2017). Fentanyl safety recommendations for first responders. https://www.whitehouse.gov/sites/whitehouse.gov/files/images/Final%20 STANDARD%20size%20of%20Fentanyl%20Safety%20Recommendations%20for%20First%20 Respond....pdf I White, J. M. and Irvine, R. J., (1999), ‘Mechanisms of fatal opioid overdose’, Addiction, 94, pp. 961–972. https://doi.org/10.1046/j.1360-0443.1999.9479612.x I Zee, S.H. and Wang, W.K., (1980), ‘A new process for the synthesis of fentanyl’, Journal of the Chinese Chemical Society, 27(4), pp. 147–149.

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Annex 1 I Images from seizures and collected samples provided to the EMCDDA

Country Image Description

Poland Seizure Date: 5 September 2017 Seizing authority: Customs Services at the Polish Post White powder; 1 package containing 495.4 grams and 1 package containing 499 grams. The package was shipped from China and had transited through Belgium before it was seized in Poland.

United Kingdom Collected sample Date: 22 August 2017 Collecting authority: TICTAC Communications Ltd.

15 / 16 TD-AS-18-001-EN-N Recommended citation:

European Monitoring Centre for Drugs and Drug Addiction (2018), EMCDDA–Europol Joint Report on a new psychoactive substance: N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl] cyclopropanecarboxamide (cyclopropylfentanyl), Joint Reports, Publications Office of the European Union, Luxembourg.

The Joint Report represents a legal document, prepared in cooperation with the Council, EMA, and Commission and is published in the original version that has not been edited.

About the EMCDDA

The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is the central source and confirmed authority on drug-related issues in Europe. For over 20 years, it has been collecting, analysing and disseminating scientifically sound information on drugs and drug addiction and their consequences, providing its audiences with an evidence-based picture of the drug phenomenon at European level.

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EMCDDA and Europol I EMCDDA–Europol 2016 Annual Report on the implementation of Council Decision 2005/387/JHA, Implementation reports, 2017

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I EMCDDA Action on new drugs: www.emcdda.europa.eu/drug-situation/new-drugs

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Luxembourg: Publications Office of the European Union PDF: ISBN 978-92-9497-254-5 doi:10.2810/06909 TD-AS-18-001-EN-N Print: ISBN 978-92-9497-255-2 doi:10.2810/857562 TD-AS-18-001-EN-C

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